tbuckley/cabot-search huggingface dataset:
Abstract 6293: Genomic characteristics of nivolumab/ipilimumab with or without CBM-588 supplementation in patients with metastatic renal cell carcinoma
Authors: Daniela V. Castro, Nazli Dizman, Zeynep B. Zengin, Jasnoor Malhotra, Luis A. Meza, Ramya Muddasani, Ameish Govindarajan, Neal S. Chawla, Alex Chehrazi-Raffle, JoAnn Hsu, Paulo G. Bergerot, Cristiane D. Bergerot, Tanya B. Dorff, Yung Lyou, Sumanta K. Pal
Journal: Cancer Research (2022)

Abstract Background: In a previous randomized phase I trial, addition of CBM-588 to the nivolumab/ipilimumab (N/I) regimen showed improved objective response rate, clinical benefit rate, and progression free survival compared to N/I alone in patients (pts) with metastatic renal cell carcinoma (mRCC; Meza et al., ASCO 2021). Furthermore, genomic alterations such as PBRM1 have been associated with clinical benefit to anti-PD-1 monotherapy in patients with mRCC (Miao et al., Science 2018). The primary aim of this study was to investigate tumor genomic characteristics according to treatment arms. Methods: We retrospectively identified pts with mRCC who received N/I alone or with CBM-588 supplementation along with whole exome and transcriptome sequencing (Ashion Analytics). Responses were measured according to RECIST v1.1. A two-tailed Fischer’s exact test was performed to compare genomic characteristics across arms. Results: In this study, 29 mRCC pts were randomized to receive N/I +/- CBM-588 and 21 (72%) pts (71% in N/I with CBM-588 arm and 29% N/I arm) had available genomic data. Within this cohort, the median age was 66.8 (range 46-90) and 71% of pts were male. Eleven (52.4%) pts had clear-cell histology and 10 (47.6%) pts had sarcomatoid features; 15 pts received N/I with CBM-588 and 6 pts received N/I alone. The most commonly mutated genes in the overall cohort were VHL (61.9%), PBRM1 (42.9%), and SETD2 (33.3%). Alterations in VHL, PBRM1, and SETD2 were seen in 66.7% vs. 73.3% (p=0.115), 50.0% vs. 40.0% (p=0.523) and 33.3% vs. 33.3% (p=0.686), in N/I vs. N/I with CBM-588 arm, respectively. Conclusions: There was no significant difference observed in clinically relevant genomic features across study arms. The clinical benefit from CBM-588 appears to be independent of tumor genomic characteristics. More extensive investigations are needed to characterize the determinants of benefit from CBM-588 supplementation. Citation Format: Daniela V. Castro, Nazli Dizman, Zeynep B. Zengin, Jasnoor Malhotra, Luis A. Meza, Ramya Muddasani, Ameish Govindarajan, Neal S. Chawla, Alex Chehrazi-Raffle, JoAnn Hsu, Paulo G. Bergerot, Cristiane D. Bergerot, Tanya B. Dorff, Yung Lyou, Sumanta K. Pal. Genomic characteristics of nivolumab/ipilimumab with or without CBM-588 supplementation in patients with metastatic renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6293.
Abstract 2886: Antigen internalization and its prevention during treatment with bispecific antibodies
Authors: Maria Klimovich, Latifa Zekri, Gundram Jung, Helmut R. Salih
Journal: Cancer Research (2022)

Abstract Antigen-mediated antibody internalization is an important factor influencing kinetics and efficacy of antibody-based therapeutics. Antibodies directed against HER2, CD20, FLT3, EGFR, CD10 and CD22 have been shown to undergo internalization upon binding to their target antigens. Although antibody-induced internalization may be desirable under some circumstances, for example in case of antibody-drug conjugates, it can subvert the therapeutic efficacy of ADCC-inducing antibodies and bispecific antibodies (bsAbs) aiming to mobilize T cells against cancer. Here we examined the turnover of PSMA, a target antigen widely used for diagnostic and therapeutic interventions in prostate cancer. As a model system, we used prostate cancer cell lines expressing varying levels of PSMA in functional analyses with our PSMAxCD3 bsAb CC-1 which is currently being evaluated in two clinical trials (NCT04104607 and NCT04496674). Antigen internalization kinetics was analyzed by flow cytometric-internalization assays and live-cell imaging of antibody internalization. These analyses revealed that surface PSMA expression is rapidly downregulated after binding of PSMAxCD3 bsAb. Internalization occured in a dose-dependent manner, with complete negativity observed at concentrations ≥0.1 µg/ml. After withdrawal of the bsAb, antigen surface levels were fully restored within 24 hours. PSMA internalization was found to be partially prevented by inhibiting clathrin-dependent endocytosis. Currently, we are screening various clinically approved clathrin-dependent endocytosis inhibitors (e.g. statins and chloroquine) to identify compounds for combinatorial approaches to prevent undesired PSMA internalization in patients receiving PSMAxCD3 bsAbs. Altogether, our results document the involvement of clathrin-dependent endocytosis in bsAbs-driven PSMA internalization and provide a basis for combinatorial approaches to increase the efficacy of PSMA-directed therapeutics. Citation Format: Maria Klimovich, Latifa Zekri, Gundram Jung, Helmut R. Salih. Antigen internalization and its prevention during treatment with bispecific antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2886.
Abstract 5212: Braf-altered microsatellite-stable metastatic colorectal cancer: A niche for immunotherapy
Authors: Feng-Che Kuan, Chung-Sheng Shi, Yu-Ying Wu, Meng-Hung Lin
Journal: Cancer Research (2022)

Abstract Background: The successful inhibition of the PD-1/PD-L1 axis and CTLA-4 has opened the era of immuno-oncology, however only a few patients with metastatic colorectal cancer (mCRC) and microsatellite instability (MSI, ~5%) derive survival benefits from these treatments. BRAF genomic alterations, mainly V600 point mutations, comprise 10-15% of cases and have a poorer prognostic phenotype. Method: The public domain genomic database (via cBioPortal and AACR Project GENIE) was used as an external control to explore the genomic make-up of BRAF-mutated and BRAF-wild mCRC tumors. The Wilcoxon sum rank test was used for the genome-wide association analysis, and the Kaplan-Meier method was used to estimate survival. Besides, clinical observations on extraordinary responses to regorafenib plus nivolumab therapy in two patients with microsatellite stable (MSS) mCRC with BRAF genomic alterations were reported. Result: The CRC cohort comprised 2,936 patients and the immune checkpoint inhibitor (ICI) treated cohort comprised 1,661 patients, of which 110 (6.6%) were CRC patients. BRAF genomic alterations (CRC versus ICI cohort: 12.4% versus 11.8%, respectively) were significantly associated with POLE and PRKDC gene mutations (p&amp;lt;0.001). The genomic signatures, such as higher mutation count (MC) (log2 [6.54 versus 3], Wilcoxon p&amp;lt;10-10) and lower fraction genome altered (FGA) (log2 [-3.62 versus -2.22], Wilcoxon p=2.08e-9) were similar to that of POLE and PRKDC in the CRC cohort. Also, BRAF genomic alterations are associated with higher mutation counts in not only MSI but MSS cohorts (p=0.033 and p&amp;lt;0.001, respectively). In the ICI cohort, BRAF-altered colorectal tumors were associated with a higher TMB (43.3 versus 7.81, Wilcoxon p=0.016). In the CRC cohort, BRAF-altered tumors were associated with poorer overall survival (median 38.04 versus &amp;gt;80 month, log rank p&amp;lt;0.0001); and in the ICI cohort, BRAF-altered colorectal tumors were associated with a trend of better overall survival after ICI treatment (median &amp;gt;80 versus 15 months, log rank p=0.121) Conclusion: BRAF-mutated malignancies represent a sub-population of MSS CRC with higher TMB, which could benefit from a combination of regorafenib and nivolumab therapy. Citation Format: Feng-Che Kuan, Chung-Sheng Shi, Yu-Ying Wu, Meng-Hung Lin. Braf-altered microsatellite-stable metastatic colorectal cancer: A niche for immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5212.
Abstract 856: Coiled-coil domain containing 3 suppresses breast cancer growth by protecting p53 from proteasome-mediated degradation
Authors: Hyemin Lee, Caiyue Li, Ji Hoon Jung, Yiwei Zhang, Jieqiong Wang, Chang Liu, Allyson M. Segall, Roger L. Sheffmaker, Shelya X. Zeng, Hua Lu
Journal: Cancer Research (2022)

Abstract Coiled-coil domain containing 3 (CCDC3) was previously shown to regulate liver lipid metabolism as a secretory protein. Our recent studies revealed an intracellular role of CCDC3 as a tumor suppressor in breast cancer (BrC). Bioinformatics datasets analysis showed that CCDC3 is under-expressed in BrCs, while its higher levels are correlated with higher overall survival and lower relapse of cancer patients. CCDC3 is positively correlated with p53 and its target genes. Ectopic CCDC3 markedly suppressed proliferation, colony formation, and xenograft tumor growth by augmenting p53 activity in BrC cells. In contrast, knockdown of endogenous CCDC3 using CRISPR led to reduction of p53 level and activity, consequently promoting the proliferation of BrC cells. Mechanistically, CCDC3 bound to the C-termini of p53 and MDM2, consequently stabilizing p53 in the nucleus and impairing MDM2 recruitment of p53 to the 26S proteosome without inhibiting p53 ubiquitination. Also, knockdown of CCDC3 caused the resistance of BrC cells to 5-FU to some degrees by alleviating p53 response to this drug. p53 induced CCDC3 expression by binding to its promoter specifically in BrC cells. Our results unveil a unique mechanism underlying CCDC3 activation of p53 in a positive feedback fashion to suppress BrC growth and suggest that CCDC3 deficiency could be a factor for drug resistance of BrCs. Citation Format: Hyemin Lee, Caiyue Li, Ji Hoon Jung, Yiwei Zhang, Jieqiong Wang, Chang Liu, Allyson M. Segall, Roger L. Sheffmaker, Shelya X. Zeng, Hua Lu. Coiled-coil domain containing 3 suppresses breast cancer growth by protecting p53 from proteasome-mediated degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 856.
Abstract 1037: Targeting the RBM38-EIF4E complex to increase wild-type p53 as a novel cancer therapeutic strategy
Authors: Chris August Lucchesi, Jin Zhang, Xinbin Chen
Journal: Cancer Research (2022)

Abstract To date, dysregulation of more than 450 RNA-binding proteins (RBPs) across a multitude of cancers has been implicated in tumorigenesis and chemoresistance. In fact, emerging evidence suggests RBPs are principal modulators of every hallmark of cancer progression. Functionally, RBPs are believed to modulate the stability, localization, and translation of transcripts encoding for virtually all known oncogenes and tumor suppressor genes. Consequently, aberrant expression of RBPs may contribute to the malignant transformation of cancer cells through enhancing the expression of oncogenes or decreasing the expression of tumors suppressor genes, such as TP53. As a potent transcription factor, TP53 is a leading regulator of numerous signaling pathways involved in tumor suppression. While mutation or deletion of TP53 contributes to tumorigenesis in more than half of all human cancers, suppression of wild-type TP53 expression also drives tumorigenesis. Thus far, multiple RBPs have been implicated in the repression of wild-type TP53, such as RNA-binding motif protein 38 (RBM38). Specifically, RBM38 interacts with eukaryotic translation initiation factor 4E (EIF4E) on the TP53 transcript, preventing EIF4E from binding to TP53 m7G cap, thus inhibiting TP53 translation. We previously demonstrated that Pep8, an 8 amino acid peptide derived from RBM38, disrupts the RBM38-EIF4E complex enhancing TP53 expression. Moreover, Pep8 alone or in combination with doxorubicin, significantly decreased tumor xenograft growth. As activation of wild-type TP53 by targeting non-genetic mechanisms that inhibit TP53 expression is a promising therapeutic tactic for malignancies that carry wild-type TP53, we are developing more efficacious Pep8 derivatives as a novel therapeutic approach for cancers that express wild-type TP53. Citation Format: Chris August Lucchesi, Jin Zhang, Xinbin Chen. Targeting the RBM38-EIF4E complex to increase wild-type p53 as a novel cancer therapeutic strategy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1037.
Abstract 1861: Trophoblast cell surface antigen 2 (TROP2) expression in human tumors: A tissue microarray study on 18,563 tumors
Authors: David Dum, Claudia Hube-Magg, Ronald Simon, Elena Bady, Tim Mandelkow, Niclas C. Blessin, Maximilian Lennartz, Guido Sauter, Sarah Minner, Andreas M. Luebke
Journal: Cancer Research (2022)

Abstract Trophoblast cell surface antigen 2 (TROP2) is the target of sacituzumab govitecan (SG), an antibody-drug conjugate that was recently approved for previously treated triple negative breast cancer and urothelial carcinomas. To comprehensively determine TROP2 expression in normal and neoplastic tissues, a tissue microarray containing 18,563 samples from 150 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. TROP2 positivity was found in most normal epithelial cell types and in 109 of 150 tumor categories, including 92 of 95 epithelial tumor categories. Particularly high rates of TROP2 positivity and highest expression levels were seen in squamous cell carcinomas of various origins and various categories of urothelial, breast, prostate, pancreatic, and ovarian cancers (&amp;gt;95% positive). High TROP2 expression was linked to advanced stage (p=0.0069) and nodal metastasis (p&amp;lt;0.0001) in colorectal cancer as well as to nodal metastasis in gastric adenocarcinoma (p=0.0246) and papillary thyroid cancer (p=0.0013). Low TROP2 expression was linked to advanced stage in urothelial carcinoma (p&amp;lt;0.0001), high pT (p=0.0024) and high grade (p&amp;lt;0.0001) in breast cancer, as well as with high grade (p=0.0005) and pT stage (p=0.0009) in papillary renal cell carcinomas. Associations between TROP2 expression and clinicopathological features were not found in clear cell renal cell carcinomas, high grade serous ovarian carcinomas, pancreatic adenocarcinomas and in endometroid endometrium carcinomas. In summary, TROP2 is abundantly expressed in a broad range of epithelial neoplasms. Both TROP2 upregulation and downregulation can be associated with cancer progression in a tumor type dependent manner. As anti-TROP2 cancer drugs have demonstrated efficiency and induce tolerable side effects they may be applicable to a broad range of tumor entities in the future. Citation Format: David Dum, Claudia Hube-Magg, Ronald Simon, Elena Bady, Tim Mandelkow, Niclas C. Blessin, Maximilian Lennartz, Guido Sauter, Sarah Minner, Andreas M. Luebke. Trophoblast cell surface antigen 2 (TROP2) expression in human tumors: A tissue microarray study on 18,563 tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1861.
Abstract 1930: Unsupervised sub-cellular segmentation of complex tissue and cell samples using highly multiplexed imaging-derived <i>a priori</i> knowledge
Authors: Bogdan Kochetov, Phoenix D. Bell, Rebecca Raphael, Benjamin J. Raymond, Brian J. Leibowitz, Jingshan Tong, Brenda Diergaarde, Jian Yu, Reetesh K. Pai, Robert E. Schoen, Lin Zhang, Aatur Singhi, Shikhar Uttam
Journal: Cancer Research (2022)

Abstract Spatial context of heterocellular interactions within solid tumor microenvironments (TMEs) is important for deciphering the mechanistic underpinnings of malignant TME phenotypes and leveraging that knowledge to improve personalized and precision medicine. Recent development of highly multiplexed imaging approaches, such as co-detection by indexing (CODEX), cyclic immunofluorescence (cycif), and imaging mass cytometry (IMC) has, for the first time, allowed deep interrogation of this heterocellular spatial complexity. Proper quantitation of this complexity, however, requires the ability to easily and accurately segment and localize cells and their sub-cellular compartments within the spatial context of the tumor microenvironment. Seminal approaches based on semi-supervised and supervised learning methods, including deep learning techniques, have been developed to segment cells and their nuclei. However, generalization of these methods to segmenting heterogenous and complex cell and tissue samples with varying resolution, magnification, and dynamic range, remains a persistent bottleneck. In case of deep learning, the requirement of large and accurate annotated datasets further adds to the challenge of seamless integration of systems-based methods in pathology and cancer research. Here, we demonstrate that by leveraging cell-compartment specific a priori knowledge captured by these imaging modalities, we can segment cells in complex tissue and cell samples in an unsupervised manner, without requiring model training. We specifically show that using nucleus and cell-membrane markers, we can accurately segment sub-cellular compartments of a diversity of tissue samples imaged at different resolutions, magnifications and dynamic ranges, and cell samples at varying levels of confluency. We also demonstrate that our method is fast. Given its ease of use, accuracy, robustness, and no requirement of large, annotated datasets, our unsupervised segmentation method fills a much-needed gap toward integration of spatial systems biology and cancer research within the convergence science paradigm. Citation Format: Bogdan Kochetov, Phoenix D. Bell, Rebecca Raphael, Benjamin J. Raymond, Brian J. Leibowitz, Jingshan Tong, Brenda Diergaarde, Jian Yu, Reetesh K. Pai, Robert E. Schoen, Lin Zhang, Aatur Singhi, Shikhar Uttam. Unsupervised sub-cellular segmentation of complex tissue and cell samples using highly multiplexed imaging-derived a priori knowledge [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1930.
Abstract 1566: Influence of age on fibroblast derived extracellular vesicles and their role in melanoma progression
Authors: Laura Hueser, Yash Chhabra, Olesia Gololobova, Mitchell Fane, Kenneth Witwer, Ashani Weeraratna
Journal: Cancer Research (2022)

Abstract Age is an important prognostic factor in cutaneous melanoma, which commonly arises in the elderly. Melanoma progression is the concerted outcome of cellular and molecular changes that occur not just within the tumor cells but also within the milieu of the stromal cells (fibroblasts, immune cells, adipocytes), collectively referred to as the tumor microenvironment (TME). Moreover, TME-secreted growth factors, cytokines, and extracellular matrix (ECM) are vital to tumor progression and therapy resistance. Aging causes remodeling of the TME that becomes conducive to melanoma progression. In addition, extracellular vesicles (EVs) have been shown to transport lipids, mRNAs and functional proteins between different cells in vitro and across tissues in vivo. EVs have also been shown to play an important role in tumor progression in different cancer types, and aging can change their composition as well as their cargo. We performed proteomics on EVs released by young and aged dermal fibroblasts, the predominant stromal cell population of melanoma TME, to investigate how aging of the cells changes the EVs released by them. Moreover, we performed functional assays to investigate what influence this will have on the tumor progression. Our study shows that EVs secreted by dermal fibroblasts change in their composition as well as their cargo adding another dimension to age-associated increase in melanoma progression, and therapy resistance. Citation Format: Laura Hueser, Yash Chhabra, Olesia Gololobova, Mitchell Fane, Kenneth Witwer, Ashani Weeraratna. Influence of age on fibroblast derived extracellular vesicles and their role in melanoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1566.
Abstract 2487: Distinct venous brain vessels provide structures for T lymphocyte recruitment to brain tumors in mouse models of intracranial melanoma
Authors: Julia M. Messmer, Manuel Piechutta, Varun Venkataramani, Chanté Mayer, Anna S. Berghoff, Daniel Hinze, Michael Hölzel, Iris Helfrich, Dirk Schadendorf, Wolfgang Wick, Matthia A. Karreman, Frank Winkler
Journal: Cancer Research (2022)

Abstract Immune checkpoint therapy has demonstrated potential for the treatment of brain metastases, but the mechanisms of lymphocyte recruitment to brain tumors are poorly understood. To monitor T cell infiltration and brain tumor growth in vivo in real time, we performed intravital microscopy of adoptively transferred and endogenous T cells in mouse models of intracranial melanoma. By spatio-temporal analysis of T cell infiltration dynamics in brain tumors we could identify a distinct type of venous blood vessels in the tumor vicinity, “peritumoral venous vessels” (PVVs). Intraluminal T cell attachment and T cell extravasation was increased at PVVs compared to intratumoral vessels. Moreover, PVVs were characterized by high perivascular T cell density, high T cell motility parameters and high expression of ICAM-1. PVVs were specifically exploited for the recruitment of T cells to melanoma brain tumors, whereas alternative T cell routes via brain structures such as brain capillaries, intratumoral blood vessels and parasagittal regions were not observed. Immune checkpoint inhibition increased T cell motility in the brain, facilitating the advance from PVV to tumor, which resulted in intracranial tumor growth inhibition. Our findings describe a distinct mechanism by which the immune system targets melanoma brain tumors, and, potentially, other intracranial pathologies. Citation Format: Julia M. Messmer, Manuel Piechutta, Varun Venkataramani, Chanté Mayer, Anna S. Berghoff, Daniel Hinze, Michael Hölzel, Iris Helfrich, Dirk Schadendorf, Wolfgang Wick, Matthia A. Karreman, Frank Winkler. Distinct venous brain vessels provide structures for T lymphocyte recruitment to brain tumors in mouse models of intracranial melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2487.